We have developed a multidisciplinary program to investigate specific genetic events and mechanisms for childhood cancer, according to a multistep mutation model with clonal evolution associated with progressive genetic instability and metastatic potential. We propose to use molecular, cytogenetic, somatic cell-biochemical genetic, and genetic-epidemiologic techniques to examine the critical primary and secondary genetic alterations in uniquely selected populations. Using these various approaches, we hope to define and characterize genetic events and associated phenotypes at each step of the pathway from the normal to the malignant cell, including distinct genes predisposing to cancer with broad or limited tissue specificity, somatic, tumor-specific acquired genetic alterations associated with tumor development, gene/environmental interactions in tumor induction, and mechanisms for tumor progression and evolution. It is our conviction that the ability to develop genetic markers for each stage of neoplastic development, and to correlate genotypic changes with phenotype, will provide new opportunities to develop strategies for intervention.